Digital Commons Network^™

Preventing Cholesterol-Induced Perk (Protein Kinase Rna-Like Endoplasmic Reticulum Kinase) Signaling In Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation, Abhijnan Chattopadhyay, Pujun Guan, Suravi Majumder, Kaveeta Kaw, Zhen Zhou, Chen Zhang, Siddharth K Prakash, Anita Kaw, L Maximillian Buja, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.

METHODS: We generated an SMC-specific

RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 …

Advances In Management And Therapeutics Of Cutaneous Basal Cell Carcinoma, Olivia M Chen, Keemberly Kim, Chelsea Steele, Kelly M Wilmas, Nader Aboul-Fettouh, Carrick Burns, Hung Quoc Doan, Sirunya Silapunt, Michael R Migden

Faculty, Staff and Student Publications

Basal cell carcinoma (BCC), the most common cancer in humans, is a malignant neoplasm of cells derived from the basal layer of the epidermis. Tumor characteristics such as histologic subtype, primary versus recurrent tumor, anatomic location, size, and patient attributes determine the risk level and acceptable treatment options. Surgical options offer histologic confirmation of tumor clearance. Standard excision provides post-treatment histologic assessment, while Mohs micrographic surgery (MMS) provides complete margin assessment intraoperatively. Additional treatment options may be employed in the correct clinical context. Small and low-risk BCCs, broad field cancerization, locally-advanced disease, metastatic disease, cosmetic concerns, or morbidity with surgical …

Whole Genome Sequence Association Analysis Of Fasting Glucose And Fasting Insulin Levels In Diverse Cohorts From The Nhlbi Topmed Program, Daniel Dicorpo, Sheila M Gaynor, Emily M Russell, Kenneth E Westerman, Laura M Raffield, Timothy D Majarian, Peitao Wu, Chloé Sarnowski, Heather M Highland, Anne Jackson, Natalie R Hasbani, Paul S De Vries, Jennifer A Brody, Bertha Hidalgo, Xiuqing Guo, James A Perry, Jeffrey R O'Connell, Samantha Lent, May E Montasser, Brian E Cade, Deepti Jain, Heming Wang, Ricardo D'Oliveira Albanus, Arushi Varshney, Lisa R Yanek, Leslie Lange, Nicholette D Palmer, Marcio Almeida, Juan M Peralta, Stella Aslibekyan, Abigail S Baldridge, Alain G Bertoni, Lawrence F Bielak, Chung-Shiuan Chen, Yii-Der Ida Chen, Won Jung Choi, Mark O Goodarzi, James S Floyd, Marguerite R Irvin, Rita R Kalyani, Tanika N Kelly, Seonwook Lee, Ching-Ti Liu, Douglas Loesch, Joann E Manson, Ryan L Minster, Take Naseri, James S Pankow, Laura J Rasmussen-Torvik, Alexander P Reiner, Muagututi'a Sefuiva Reupena, Elizabeth Selvin, Jennifer A Smith, Daniel E Weeks, Huichun Xu, Jie Yao, Wei Zhao, Stephen Parker, Alvaro Alonso, Donna K Arnett, John Blangero, Eric Boerwinkle, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, Ravindranath Duggirala, Jiang He, Susan R Heckbert, Sharon L R Kardia, Ryan W Kim, Charles Kooperberg, Simin Liu, Rasika A Mathias, Stephen T Mcgarvey, Braxton D Mitchell, Alanna C Morrison, Patricia A Peyser, Bruce M Psaty, Susan Redline, Alan R Shuldiner, Kent D Taylor, Ramachandran S Vasan, Karine A Viaud-Martinez, Jose C Florez, James G Wilson, Robert Sladek, Stephen S Rich, Jerome I Rotter, Xihong Lin, Josée Dupuis, James B Meigs, Jennifer Wessel, Alisa K Manning

Faculty, Staff and Student Publications

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, …

Plasma Amyloid-Β Dynamics In Late-Life Major Depression: A Longitudinal Study, Nunzio Pomara, Davide Bruno, Chelsea Reichert Plaska, Jaime Ramos-Cejudo, Ricardo S Osorio, Anilkumar Pillai, Bruno P Imbimbo, Henrik Zetterberg, Kaj Blennow

Faculty, Staff and Student Publications

Depressed individuals are twice as likely to develop Alzheimer’s disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β1-40 (Aβ40) and amyloid-β1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly …

Maternal Iron Deficiency Programs Rat Offspring Hypertension In Relation To Renin-Angiotensin System And Oxidative Stress, Ya-Hui Chang, Wan-Hsuan Chen, Chung-Hao Su, Hong-Ren Yu, You-Lin Tain, Li-Tung Huang, Jiunn-Ming Sheen

Faculty, Staff and Student Publications

Hypertension is an important public health challenge, affecting up to 30-50% of adults worldwide. Several epidemiological studies indicate that high blood pressure originates in fetal life-the so-called programming effect or developmental origin of hypertension. Iron-deficiency anemia has become one of the most prevalent nutritional problems globally. Previous animal experiments have shown that prenatal iron-deficiency anemia adversely affects offspring hypertension. However, the underlying mechanism remains unclear. We used a maternal low-iron diet Sprague Dawley rat model to study changes in blood pressure, the renal renin-angiotensin system, oxidative stress, inflammation, and sodium transporters in adult male offspring. Our study revealed that 16-week-old …

Advances In Cutaneous Squamous Cell Carcinoma Management, Carrick Burns, Shelby Kubicki, Quoc-Bao Nguyen, Nader Aboul-Fettouh, Kelly M Wilmas, Olivia M Chen, Hung Quoc Doan, Sirunya Silapunt, Michael R Migden

Faculty, Staff and Student Publications

cSCC is increasing in prevalence due to increased lifespans and improvements in survival for conditions that increase the risk of cSCC. The absolute mortality of cSCC exceeds melanoma in the United States and approaches that of melanoma worldwide. This review presents significant changes in the management of cSCC, focusing on improvements in risk stratification, new treatment options, optimization of existing treatments, and prevention strategies. One major breakthrough in cSCC treatment is the advent of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), which have ushered in a renaissance in the treatment of …

Targeting De Novo Lipogenesis And The Lands Cycle Induces Ferroptosis In Kras-Mutant Lung Cancer, Caterina Bartolacci, Cristina Andreani, Gonçalo Vale, Stefano Berto, Margherita Melegari, Anna Colleen Crouch, Dodge L Baluya, George Kemble, Kurt Hodges, Jacqueline Starrett, Katerina Politi, Sandra L Starnes, Daniele Lorenzini, Maria Gabriela Raso, Luisa M Solis Soto, Carmen Behrens, Humam Kadara, Boning Gao, Ignacio I Wistuba, John D Minna, Jeffrey G Mcdonald, Pier Paolo Scaglioni

Faculty, Staff and Student Publications

Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, …

Molecular Profiles Of Serum-Derived Extracellular Vesicles In High-Grade Serous Ovarian Cancer, Li Zhao, Sara Corvigno, Shaolin Ma, Joseph Celestino, Nicole D Fleming, Richard A Hajek, Adrian Lankenau Ahumada, Nicholas B Jennings, Erika J Thompson, Hongli Tang, Shannon N Westin, Amir A Jazaeri, Jianhua Zhang, P Andrew Futreal, Anil K Sood, Sanghoon Lee

Faculty, Staff and Student Publications

Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified …

Tdp1-Independent Pathways In The Process And Repair Of Top1-Induced Dna Damage, Huimin Zhang, Yun Xiong, Dan Su, Chao Wang, Mrinal Srivastava, Mengfan Tang, Xu Feng, Min Huang, Zhen Chen, Junjie Chen

Faculty, Staff and Student Publications

Anticancer drugs, such as camptothecin (CPT), trap topoisomerase I (TOP1) on DNA and form TOP1 cleavage complexes (TOP1cc). Alternative repair pathways have been suggested in the repair of TOP1cc. However, how these pathways work with TDP1, a key repair enzyme that specifically hydrolyze the covalent bond between TOP1 catalytic tyrosine and the 3'-end of DNA and contribute to the repair of TOP1cc is poorly understood. Here, using unbiased whole-genome CRISPR screens and generation of co-deficient cells with TDP1 and other genes, we demonstrate that MUS81 is an important factor that mediates the generation of excess double-strand breaks (DSBs) in TDP1 …

Cranial Base Synchondrosis Lacks Pthrp-Expressing Column-Forming Chondrocytes, Shawn A Hallett, Annabelle Zhou, Curtis Herzog, Ariel Arbiv, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

The cranial base contains a special type of growth plate termed the synchondrosis, which functions as the growth center of the skull. The synchondrosis is composed of bidirectional opposite-facing layers of resting, proliferating, and hypertrophic chondrocytes, and lacks the secondary ossification center. In long bones, the resting zone of the epiphyseal growth plate houses a population of parathyroid hormone-related protein (PTHrP)-expressing chondrocytes that contribute to the formation of columnar chondrocytes. Whether PTHrP+ chondrocytes in the synchondrosis possess similar functions remains undefined. Using Pthrp-mCherry knock-in mice, we found that PTHrP+ chondrocytes predominantly occupied the lateral wedge-shaped area of the synchondrosis, unlike …

A Method For Bridging Population-Specific Genotypes To Detect Gene Modules Associated With Alzheimer's Disease, Yulin Dai, Peilin Jia, Zhongming Zhao, Assaf Gottlieb

Faculty, Staff and Student Publications

BACKGROUND: Genome-wide association studies have successfully identified variants associated with multiple conditions. However, generalizing discoveries across diverse populations remains challenging due to large variations in genetic composition. Methods that perform gene expression imputation have attempted to address the transferability of gene discoveries across populations, but with limited success.

METHODS: Here, we introduce a pipeline that combines gene expression imputation with gene module discovery, including a dense gene module search and a gene set variation analysis, to address the transferability issue. Our method feeds association probabilities of imputed gene expression with a selected phenotype into tissue-specific gene-module discovery over protein interaction …

Cranial Base Synchondrosis: Chondrocytes At The Hub, Shawn A Hallett, Wanida Ono, Renny T Franceschi, Noriaki Ono

Faculty, Staff and Student Publications

The cranial base is formed by endochondral ossification and functions as a driver of anteroposterior cranial elongation and overall craniofacial growth. The cranial base contains the synchondroses that are composed of opposite-facing layers of resting, proliferating and hypertrophic chondrocytes with unique developmental origins, both in the neural crest and mesoderm. In humans, premature ossification of the synchondroses causes midfacial hypoplasia, which commonly presents in patients with syndromic craniosynostoses and skeletal Class III malocclusion. Major signaling pathways and transcription factors that regulate the long bone growth plate-PTHrP-Ihh, FGF, Wnt, BMP signaling and Runx2-are also involved in the cranial base synchondrosis. Here, …

The Origin Of Bladder Cancer From Mucosal Field Effects, Jolanta Bondaruk, Roman Jaksik, Ziqiao Wang, David Cogdell, Sangkyou Lee, Yujie Chen, Khanh Ngoc Dinh, Tadeusz Majewski, Li Zhang, Shaolong Cao, Feng Tian, Hui Yao, Paweł Kuś, Huiqin Chen, John N Weinstein, Neema Navai, Colin Dinney, Jianjun Gao, Dan Theodorescu, Christopher Logothetis, Charles C Guo, Wenyi Wang, David Mcconkey, Peng Wei, Marek Kimmel, Bogdan Czerniak

Faculty, Staff and Student Publications

Whole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of the process. An aberrant methylation/expression of multiple HOX genes signified dysregulation of the differentiation program. We identified three types of mutations based on their geographic distribution. The most common were mutations restricted to individual mucosal samples that targeted uroprogenitor cells. Two types of mutations were associated with clonal expansion and involved large areas of …

Alphafold2 And Cryoem: Revisiting Cryoem Modeling In Near-Atomic Resolution Density Maps, Corey F Hryc, Matthew L Baker

Faculty, Staff and Student Publications

With the advent of new artificial intelligence and machine learning algorithms, predictive modeling can, in some cases, produce structures on par with experimental methods. The combination of predictive modeling and experimental structure determination by electron cryomicroscopy (cryoEM) offers a tantalizing approach for producing robust atomic models of macromolecular assemblies. Here, we apply AlphaFold2 to a set of community standard data sets and compare the results with the corresponding reference maps and models. Moreover, we present three unique case studies from previously determined cryoEM density maps of viruses. Our results show that AlphaFold2 can not only produce reasonably accurate models for …

Cd11bhigh B Cells Increase After Stroke And Regulate Microglia: Cd11bhigh B Cells Increase After Stroke And Regulate Mg, Janelle M Korf, Pedram Honarpisheh, Eric C Mohan, Anik Banerjee, Maria P Blasco-Conesa, Parisa Honarpisheh, Gary U Guzman, Romeesa Khan, Bhanu P Ganesh, Amy L Hazen, Juneyoung Lee, Aditya Kumar, Louise D Mccullough, Anjali Chauhan

Faculty, Staff and Student Publications

Recent studies have highlighted the deleterious contributions of B cells to post-stroke recovery and cognitive decline. Different B cell subsets have been proposed based on expression levels of transcription factors (e.g. T-bet) as well as specific surface proteins. CD11b (α-chain of integrin) is expressed by several immune cell types and is involved in regulation of cell motility, phagocytosis, and other essential functions of host immunity. Although B cells express CD11b, the CD11b^high subset of B cells has not been well characterized, especially in immune dysregulation seen with aging and after stroke. Here, we investigate the role of CD11b^{high …}

Gut Bacterial Isoamylamine Promotes Age-Related Cognitive Dysfunction By Promoting Microglial Cell Death, Yun Teng, Jingyao Mu, Fangyi Xu, Xiangcheng Zhang, Mukesh K Sriwastva, Qiaohong M Liu, Xiaohong Li, Chao Lei, Kumaran Sundaram, Xin Hu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Eric C Rouchka, Xiang Zhang, Jun Yan, Michael L Merchant, Huang-Ge Zhang

Faculty, Staff and Student Publications

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. …

Renin-Angiotensin System In Huntington's Disease: Evidence From Animal Models And Human Patients, Lucas M Kangussu, Natalia P Rocha, Priscila A C Valadão, Thatiane C G Machado, Kívia B Soares, Julliane V Joviano-Santos, Leigh B Latham, Gabriela D Colpo, Ana Flávia Almeida-Santos, Erin Furr Stimming, Ana Cristina Simões E Silva, Antônio L Teixeira, Aline Silva Miranda, Cristina Guatimosim

Faculty, Staff and Student Publications

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside …

Multi-Modal Molecular Programs Regulate Melanoma Cell State, Miles C Andrews, Junna Oba, Chang-Jiun Wu, Haifeng Zhu, Tatiana Karpinets, Caitlin A Creasy, Marie-Andrée Forget, Xiaoxing Yu, Xingzhi Song, Xizeng Mao, A Gordon Robertson, Gabriele Romano, Peng Li, Elizabeth M Burton, Yiling Lu, Robert Szczepaniak Sloane, Khalida M Wani, Kunal Rai, Alexander J Lazar, Lauren E Haydu, Matias A Bustos, Jianjun Shen, Yueping Chen, Margaret B Morgan, Jennifer A Wargo, Lawrence N Kwong, Cara L Haymaker, Elizabeth A Grimm, Patrick Hwu, Dave S B Hoon, Jianhua Zhang, Jeffrey E Gershenwald, Michael A Davies, P Andrew Futreal, Chantale Bernatchez, Scott E Woodman

Faculty, Staff and Student Publications

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate …

Dissecting The Treatment-Naive Ecosystem Of Human Melanoma Brain Metastasis, Jana Biermann, Johannes C Melms, Amit Dipak Amin, Yiping Wang, Lindsay A Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A Ibarra-Arellano, Massimo Andreatta, Benjamin T Fullerton, Kristjan H Gretarsson, Varun Sahu, Vaibhav S Mangipudy, Trang T T Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D Koch, Matei Banu, Nelson Humala, Aayushi Mahajan, Zachary H Walsh, Shivem B Shah, Daniel H Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M Luoma, Joseph Driver, Matthew Ingham, Shaheer A Khan, Suthee Rapisuwon, Craig L Slingluff, Thomas Eigentler, Martin Röcken, Richard Carvajal, Michael B Atkins, Michael A Davies, Albert Agustinus, Samuel F Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z Macosko, Fei Chen, Gary K Schwartz, Benjamin Izar

Faculty, Staff and Student Publications

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant …

Lncrna-Associated Genetic Etiologies Are Shared Between Type 2 Diabetes And Cancers In The Uae Population, Roberta Giordo, Rida Gulsha, Sarah Kalla, George A Calin, Leonard Lipovich

Faculty, Staff and Student Publications

Numerous epidemiological studies place patients with T2D at a higher risk for cancer. Many risk factors, such as obesity, ageing, poor diet and low physical activity, are shared between T2D and cancer; however, the biological mechanisms linking the two diseases remain largely unknown. The advent of genome wide association studies (GWAS) revealed large numbers of genetic variants associated with both T2D and cancer. Most significant disease-associated variants reside in non-coding regions of the genome. Several studies show that single nucleotide polymorphisms (SNPs) at or near long non-coding RNA (lncRNA) genes may impact the susceptibility to T2D and cancer. Therefore, the …

Tp53 Copy Number And Protein Expression Inform Mutation Status Across Risk Categories In Acute Myeloid Leukemia, Mehrnoosh Tashakori, Tapan Kadia, Sanam Loghavi, Naval Daver, Rashmi Kanagal-Shamanna, Sherry Pierce, Dawen Sui, Peng Wei, Farnoosh Khodakarami, Zhenya Tang, Mark Routbort, Carol A Bivins, Elias J Jabbour, L Jeffrey Medeiros, Kapil Bhalla, Hagop M Kantarjian, Farhad Ravandi, Joseph D Khoury

Faculty, Staff and Student Publications

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as …

Drug-Target Network Study Reveals The Core Target-Protein Interactions Of Various Covid-19 Treatments, Yulin Dai, Hui Yu, Qiheng Yan, Bingrui Li, Andi Liu, Wendao Liu, Xiaoqian Jiang, Yejin Kim, Yan Guo, Zhongming Zhao

Faculty, Staff and Student Publications

The coronavirus disease 2019 (COVID-19) pandemic has caused a dramatic loss of human life and devastated the worldwide economy. Numerous efforts have been made to mitigate COVID-19 symptoms and reduce the death rate. We conducted literature mining of more than 250 thousand published works and curated the 174 most widely used COVID-19 medications. Overlaid with the human protein-protein interaction (PPI) network, we used Steiner tree analysis to extract a core subnetwork that grew from the pharmacological targets of ten credible drugs ascertained by the CTD database. The resultant core subnetwork consisted of 34 interconnected genes, which were associated with 36 …

A Spatiotemporal Map Of Reading Aloud, Oscar Woolnough, Cristian Donos, Aidan Curtis, Patrick S Rollo, Zachary J Roccaforte, Stanislas Dehaene, Simon Fischer-Baum, Nitin Tandon

Faculty, Staff and Student Publications

Reading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans (26 male, 20 female) as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband γ activity varies with multiple word attributes critical to reading speed: lexicality, word frequency, and orthographic neighborhood. We found that lexicality is encoded …

Macrophage Migration Inhibitory Factor (Mif) Makes Complex Contributions To Pain-Related Hyperactivity Of Nociceptors After Spinal Cord Injury, Alexis Bavencoffe, Emily A Spence, Michael Y Zhu, Anibal Garza-Carbajal, Kerry E Chu, Ona E Bloom, Carmen W Dessauer, Edgar T Walters

Faculty, Staff and Student Publications

Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms are often assumed to be in the CNS, rodent studies have revealed mechanistic contributions from primary nociceptors. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity that promotes ongoing pain. A major question is whether extrinsic chemical signals help to drive ongoing electrical activity after SCI. People living with SCI exhibit acute and chronic elevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models. Probable nociceptors isolated from male rats and exposed …

Webcsea: Web-Based Cell-Type-Specific Enrichment Analysis Of Genes, Yulin Dai, Ruifeng Hu, Andi Liu, Kyung Serk Cho, Astrid Marilyn Manuel, Xiaoyang Li, Xianjun Dong, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Human complex traits and common diseases show tissue- and cell-type- specificity. Recently, single-cell RNA sequencing (scRNA-seq) technology has successfully depicted cellular heterogeneity in human tissue, providing an unprecedented opportunity to understand the context-specific expression of complex trait-associated genes in human tissue-cell types (TCs). Here, we present the first web-based application to quickly assess the cell-type-specificity of genes, named Web-based Cell-type Specific Enrichment Analysis of Genes (WebCSEA, available at https://bioinfo.uth.edu/webcsea/). Specifically, we curated a total of 111 scRNA-seq panels of human tissues and 1,355 TCs from 61 different general tissues across 11 human organ systems. We adapted our previous decoding tissue-specificity …

Modeling The Prognostic Impact Of Circulating Tumor Cells Enumeration In Metastatic Breast Cancer For Clinical Trial Design Simulation, Lorenzo Gerratana, Jean-Yves Pierga, James M Reuben, Andrew A Davis, Firas H Wehbe, Luc Dirix, Tanja Fehm, Franco Nolé, Rafael Gisbert-Criado, Dimitrios Mavroudis, Salvatore Grisanti, Jose A Garcia-Saenz, Justin Stebbing, Carlos Caldas, Paola Gazzaniga, Luis Manso, Rita Zamarchi, Marta Bonotto, Angela Fernandez De Lascoiti, Leticia De Mattos-Arruda, Michail Ignatiadis, Maria-Teresa Sandri, Daniele Generali, Carmine De Angelis, Sarah-Jane Dawson, Wolfgang Janni, Vicente Carañana, Sabine Riethdorf, Erich-Franz Solomayer, Fabio Puglisi, Mario Giuliano, Klaus Pantel, François-Clément Bidard, Massimo Cristofanilli

Faculty, Staff and Student Publications

Despite the strong prognostic stratification of circulating tumor cells (CTCs) enumeration in metastatic breast cancer (MBC), current clinical trials usually do not include a baseline CTCs in their design. This study aimed to generate a classifier for CTCs prognostic simulation in existing datasets for hypothesis generation in patients with MBC. A K-nearest neighbor machine learning algorithm was trained on a pooled dataset comprising 2436 individual MBC patients from the European Pooled Analysis Consortium and the MD Anderson Cancer Center to identify patients likely to have CTCs ≥ 5/7 mL blood (StageIVaggressive vs StageIVindolent). The model had a 65.1% accuracy and …

Deep Learning-Based Nlp Data Pipeline For Ehr-Scanned Document Information Extraction, Enshuo Hsu, Ioannis Malagaris, Yong-Fang Kuo, Rizwana Sultana, Kirk Roberts

Faculty, Staff and Student Publications

OBJECTIVE: Scanned documents in electronic health records (EHR) have been a challenge for decades, and are expected to stay in the foreseeable future. Current approaches for processing include image preprocessing, optical character recognition (OCR), and natural language processing (NLP). However, there is limited work evaluating the interaction of image preprocessing methods, NLP models, and document layout.

MATERIALS AND METHODS: We evaluated 2 key indicators for sleep apnea, Apnea hypopnea index (AHI) and oxygen saturation (SaO

RESULTS: Our proposed method using ClinicalBERT reached an AUROC of 0.9743 and document accuracy of 94.76% for AHI, and an AUROC of 0.9523 and document …

Muc1 And Polarity Markers Inadl And Scrib Identify Salivary Ductal Cells, D Wu, P J Chapela, C M L Barrows, D A Harrington, D D Carson, R L Witt, N G Mohyuddin, S Pradhan-Bhatt, M C Farach-Carson

Faculty, Staff and Student Publications

Current treatments for xerostomia/dry mouth are palliative and largely ineffective. A permanent clinical resolution is being developed to correct hyposalivation using implanted hydrogel-encapsulated salivary human stem/progenitor cells (hS/PCs) to restore functional salivary components and increase salivary flow. Pluripotent epithelial cell populations derived from hS/PCs, representing a basal stem cell population in tissue, can differentiate along either secretory acinar or fluid-transporting ductal lineages. To develop tissue-engineered salivary gland replacement tissues, it is critical to reliably identify cells in tissue and as they enter these alternative lineages. The secreted protein α-amylase, the transcription factor MIST1, and aquaporin-5 are typical markers for acinar …

Prevalence And Clustering Of Congenital Heart Defects Among Boys With Hypospadias, Melissa A Richard, Jenil Patel, Renata H Benjamin, Emine Bircan, Stephen J Canon, Lisa K Marengo, Mark A Canfield, A J Agopian, Philip J Lupo, Wendy N Nembhard

Faculty, Staff and Student Publications

IMPORTANCE: Hypospadias is a common birth defect of the male urinary tract that may be isolated or may co-occur with other structural malformations, including congenital heart defects (CHDs). The risk for co-occurring CHDs among boys with hypospadias remains unknown, which limits screening and genetic testing strategies.

OBJECTIVE: to characterize the risk of major CHDs among boys born with hypospadias.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from population-based birth defect surveillance programs on all male infants born in 11 US states from January 1, 1995, to December 31, 2014. Statistical analysis was performed from September 2, 2020, …

Cas9/Nickase-Induced Allelic Conversion By Homologous Chromosome-Templated Repair In Drosophila Somatic Cells, Sitara Roy, Sara Sanz Juste, Marketta Sneider, Ankush Auradkar, Carissa Klanseck, Zhiqian Li, Alison Henrique Ferreira Julio, Victor Lopez Del Amo, Ethan Bier, Annabel Guichard

Faculty, Staff and Student Publications

Repair of double-strand breaks (DSBs) in somatic cells is primarily accomplished by error-prone nonhomologous end joining and less frequently by precise homology-directed repair preferentially using the sister chromatid as a template. Here, a